Hit-to-lead optimization of a benzene sulfonamide series for potential antileishmanial agents

A series of benzene sulphonamides with good potency and selectivity against Leishmania spp. intracellular amastigotes was identified by high-throughput screening. Approximately 200 compounds were synthesized as part of a hit-to-lead optimization program. The potency of the series appears to be stron...

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Bibliographic Details
Published in:MedChemComm 2020-11, Vol.11 (11), p.1267-1274
Main Authors: Koovits, Paul J, Dessoy, Marco A, Matheeussen, An, Maes, Louis, Caljon, Guy, Ferreira, Leonardo L. G, Chelucci, Rafael C, Michelan-Duarte, Simone, Andricopulo, Adriano D, Campbell, Simon, Kratz, Jadel M, Mowbray, Charles E, Dias, Luiz C
Format: Article
Language:English
Subjects:
Amastigotes
Antileishmanial agents
Benzene
Chemistry
High-throughput screening
Hydrocarbons
Lipophilicity
Optimization
Pharmacokinetics
Selectivity
Sulfonamides
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Summary:A series of benzene sulphonamides with good potency and selectivity against Leishmania spp. intracellular amastigotes was identified by high-throughput screening. Approximately 200 compounds were synthesized as part of a hit-to-lead optimization program. The potency of the series appears to be strongly dependent on lipophilicity, making the identification of suitable orally available candidates challenging due to poor pharmacokinetics. Despite not identifying a clinical candidate, a likely solvent exposed area was found, best exemplified in compound 29 . Ongoing detailed mode-of-action studies may provide an opportunity to use target-based medicinal chemistry to overcome the issues with the current series. A series of benzene sulphonamides with good potency and selectivity against Leishmania spp. intracellular amastigotes was identified by high-throughput screening.
ISSN:2632-8682
2040-2503
2632-8682
2040-2511
DOI:10.1039/d0md00165a